Interaction between angiotensin II, osteoprotegerin, and peroxisome proliferator-activated receptor-gamma in abdominal aortic aneurysm.
OBJECTIVE
Osteoprotegerin (OPG) has been associated with abdominal aortic aneurysm (AAA) expansion. Angiotensin II (AngII) receptor blockade has been shown to reduce OPG expression in human AAA tissue. Interaction between vascular AngII and OPG was further examined using cell culture and the AngII-infused ApoE(-/-) mouse AAA model. The ability of peroxisome proliferator-activated receptor-gamma (PPARgamma) activation to target OPG as potential therapy for AAA was also investigated.


RESULTS
Human aortic smooth muscle cells (AoSMC) exposed to AngII exhibited dose-dependent increase in the production OPG. A 3-fold increase in suprarenal aortic concentration of OPG was observed in AngII-infused ApoE(-/-) mice. AngII type 1 receptor expression in human AAA tissue, and AoSMC in vitro, was stimulated up 4-fold in the presence of OPG. This effect in AoSMC was counteracted in the presence of the PPARgamma ligand, pioglitazone. Addition of PPARgamma ligand to cultured human AAA explant reduced OPG secretion by 60% and tissue concentration of OPG and metalloproteinase 9 by 2- and 3-fold, respectively. Administration of pioglitazone to AngII-infused ApoE(-/-) mice significantly reduced aortic concentrations of OPG and metalloproteinase 9.


CONCLUSIONS
These data support an interaction between AngII and OPG in aneurysm formation. Activation of PPARgamma may have a role in treatment of AAA.
Moran
Corey S
CS
Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, Australia.
Cullen
Bradford
B
Campbell
Julie H
JH
Golledge
Jonathan
J
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology*; D001057:Apolipoproteins E / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053244:Osteoprotegerin / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis / Q000502:physiology
D001057:Apolipoproteins E; D015850:Interleukin-6; D053244:Osteoprotegerin; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D020780:Matrix Metalloproteinase 9